3-substituted 1, 4-naphthoquinones



Patented Mar. 18, 1952 2,589,686 ICE 3 -SUBSTITUTED 1,4 -NAPHTHOQUIN ONES George Fawaz, Beirut, Lebanon, assignor to Research Corporation, NewYork, N. Y., a corporation of New York No Drawing. Application January24, 1950, Serial No. 140,350

4 Claims.

This invention pertains to a new and useful method for the preparationof 1,4-naphthoquin'ones substituted in the 3-position by alkyl andserious disadvantage that one of two moles of carboxyalkyl groups thatcan be converted by-= known methods into 2-hydroxy-3-substituted1,4-naphthoquinones of high biological potency and important uses.

A large number of 2-hydroxy-3-alkyl-l,4 naphthoquinones have beeninvestigated for antimalarial activity and many of them have been foundto exhibit high suppressive, prophylactic, and curative activity againstavian malarial infections [L. F. Fieser, M. T. Lefller and co- 'worlers, J. Am. Chem. Soc., 70, 3151 (1948);

L. F. Fieser and A. P. Richardson, ibid., 70, 3156 (1948) Those2-hydroxy-1,4-naphthoquinones that are substituted in the 3-position byan alkyl group, or by a cycloalkylalky or an arylalkyl group, do notappear suitable for human therapy because in man they suffer rapidmetabolic degradation to less active or inactive quinones in which theside chain has been oxidized or oxygenated [Fieser, Chang, Dauben,Heidelberger, Heymann and Seligman, J. Pharm. Exptl. Therap., 94, 85(1948)]. Fortunately this fault can be correcte by introduction, in thecourse of synthesis, of a suitable oxygen function in a hydrocarbon sidechain of size adequate to provide satisfactory biological potency. Thusthe most satisfactory curative drug of the series thus far developed hasa side chain of 19 carbon atoms containing a hydroxyl group now calledlapinone.

CsHu-Il The synthetic method heretofore most widely used utilizes thereaction of alkylation of 2-hydroxy-l,4-naphthoquinone with the peroxideof an acid [Fieser, Lefiier and co-workers, J. Am. Chem. So 70,3174-3215 (1948); Fieser, U. S. Patent 2,398,418]. The synthesis isshort and the reaction afiords a convenient method of preparing smallsamples of a large number of compounds for exploration of therelationship of structure to'biological activity. For manufacturingpurposes, peroxide alkylation suffers the the intermediate acid iswasted and that the yield is often far short of that theoreticallyrealizable. Thus yields of quinones of type I, which are useful asinsecticides, are only moderate, and still less favorable results areobtained in the I II synthesis of carboxyalkyl derivatives such as II,which was obtained in this way in small quantity as an intermediate[Fieser and R. B. Turner, J. Am. Chem. Soc., 69, 2338 (1947)] forsynthesis of lapinone [Fieser and G. Fawaz, J. Am. Chem. Soc, 70, 3211(1948) In the latter case therequired peroxide has to be made, withconsiderable labor and loss, from sebacic acid through ethyl hydrogensebacate and ethyl sebacyl chloride and the alkylation proceeds verypoorly.

. The new synthesis here disclosed represents an entirely difi'erentapproach; it involves no peroxide alkylation step and does not require acostly, preformed naphthoquinone as starting material. Instead, thequinone ring is formed, in a convenient and novel manner; after the sidechain has been introduced. The starting materials are abundantlyavailable substances: a-naphthol and a free fatty or a free dibasicacid. The reactions are well suited to operation on a manufacturingscale. In brief, the steps for synethesis of a 2-hydroxy-Z-alkyl-1,4-naphthoquinone are as follows: a-naphthol isacylated at the 2-position with a free acid in presence of a catalyst togive 2,589,686 3 4 V with chromic acid. A hydroxyl group is then Thedried material is then boiled with 400 cc. of introduced at theremaining free position in the acetic acid and the solution filteredthrough a quinone ring by one of the known methods, such hot funnel froman undissolved residue consistas through the 2,3-oxide lFieser, U. S.Patent ing mainiy oi sebacoyl-bis-naphthol. 2,312,535], or a 3-haloderivative lFieser, 'J. Am. The remove further traces of thebis-product, Chem. 800., '70, 3165 (1948)]. The same method the crudesebacoylnaphthol that crystallizes from is applicable to the preparationof quinones havthe acetic acid filtrate may be treated in one of ing acarboxyalkyl side chain. two ways. (a) It is boiled five minutes withten Lauroyl, myricoyl, cyclohcxylbutyryl and reparts of ethyl acetateand the solution is filtered lated groups can be introduced at the2-position n hot from a residue consisting of monoand bisin high yieldby condensation of the appropriate product; the filtrate on coolingdeposits 90-100 g. acid with e-naphthol in the presence of boron(40-44%) of crystals melting at 136-137 C. to a fluoride etherate. Whena-naphthol is Conclear fluid. (b) The crude acid is boiled for at densedwith sebacic acid under catalysis by zinc least ten minutes with 8%sodium bicarbonate chloride 2-sebacoyl-l-naphthol (VII) is the (1.5 g.of bicarbonate per g. of material) and the chief product and can be 7solution filtered hot from the bis-product and on on o A A cowiioio inZn i WITCH fioioozciei cnmcoioini VII VIII x i i oni)io oicini.oni)iooin I l e l l V on H i t x1 II separated from a small amount ofthe bis-prod: neutralized cautiously while hot with hydrouct andobtainedeasily in 40-44% yield. chloric acid. Crystallization from acetic acidClemmensen reduction of the ket-o acid VII in then gives material of thesame quality and yield alcoholic solution affords the reduced esterVIII, as in (a), The pure acid melts at 1375-139 C. and this can beconverted into the quinone ester EXAMPLE 2 IX by oxidation with chromicacid or chromic anhydride. The oxide in XI is obtained in high Ethyl w-1Adwphthoquinonflldg -dewn0ate (X) yield .and can be converted by trea tWith A solution of 100 g. of 2-sebacoyl-l-naphthol 96% sulfuric acid andsubsequent acid hydrolysis in 2 l. of 95% alcohol is treated with 500cc. of into the y ph oquinonyldecanoic acid 36% hydrochloric acid in 100g. of freshly poured X. Hooker oxidation by the improved two-step zincamalgamated by shaking for fifteen minutes D OG S [Fieser d Chem- C-,with 10 g. of mercuric chloride in 8 cc. of 36% 3215 (1948):] isconducted satisfactorily on a hydrochloric acid and 140 cc. of Water. Thlarge scale and affords the desired intermediate ture is refluxedvigorously for seven hours, diluty y p q incnylnonanoic acid (II). edwith 2.5 volumes of water, and the oily ethyl Acid chlorides, alkylesters, or a-naphthol w-(l-hYdIOXY- 2 -naphthyl) decanoate (VIII) esterscan be used as well in the condensation but to collected by etherextraction. After removal of ofier no advantages over the moreaccessible free last traces of ether in vacuum at a temperature acids, 7not exceeding C., the oil (about g.) is dis- The synthesis is capable ofwide variation and solved in 800 cc. of acetic acid and treated with aaffords a practicable route to a variety of alkyl solution of g. ofchromic anhydride in '75 cc. and carboxyalkyl derivatives hithertoaccessible 55 each of water and acetic acid, added over thirty inquantity only with considerable difficulty. The minutes. The temperaturei maintained at 50 examples given merely illustrate the principles of C.by cooling during the addition; when the temthe invention. peraturebegins to drop the flask is placed in a EXAMPLE 1 the starting materialand size of batch. The z sebacoyz l naphthol (VII) (lo green solution isthen diluted with 2.5 volumes of water and the dark sticky precipitateis collected A -ep q of scheme acid 18 melted in a the next day,crystallized from 250 cc. of acetic fl s q pp d Wlth a ter d acid-Water(5:1), and the yellow needles Washed ical stirrer and the temperature isbrought to with 100 cc. of acetic acid-water (1:1); M. P.

-137 C. and maintained at this point during (35 7347 (j The yield variesmm I quality of addition of g. of freshly Iused and finely th startingmaterial and size of batch The powdered zinc chlorid fol o ed y 0' g. of11- average yield in several 100-g. runs was 32 g. naphtholintroduced infive minutes." Heating (29.5% overall from the keto acid). The pure andstirring are continued for thirty minute ester crystallizes from aceticacid or methanol in longer and the melt is poured into water With Tolong yellow needles, M. P. Vi-75C. vigorous stirring. The granularproduct is collected and washed with hot water and then with EXAMPLE 3 alittle cold alcohol; it is then boiled with 500 cc. Ethyl (3 hydmxymphmoqumonylof alcohol, cooled, filtered, and washed with coldz-l'decanaaw Oxide (XI) alcohol until the filtrate is colorless(300:-;cc.). 75 'Td Ia solution of 100 g. of the q uinone estelin 500cc. of dioxane, a solution of 30 g. of sodium carbonate in 170 cc. ofwater and 70- cc. of hydrogen peroxide are added, and the mixture is w(3 hydrowy 1,4 naphthoquinoyl 2) decanoic acid (XII) One hundred g. ofthe above oxide ester-isslowly stirred into 400 cc. of 96% sulfuric acidthat has been chilled to 5 C. The mixture is stirred at room temperaturefor one-half hour to effect complete solution (yellow changing to deepred) and then poured into 600 cc. of ice and- 2 l. of acetic acid andheated on the steam bath for two hours. furic acid gives a mixture ofacid and ester and the purpose of the after treatment is to eifectcomplete hydrolysis; a little ester may appear as an oil at the startbut later dissolves.) The dark solution on cooling deposits dull yellowneedles (88.8 g.) M. P. 93-95 C. to a dark liquid. Crystallization fromacetic acid gives light yellow needles, M. P. 104-105 C. (yellow melt);yield (dried to constant weight) 86.8 g. (94%). v

EXAMPLE 5 w (3 hydrory 1,4 naphtho'quinonyl 2)- nonanoic acid (11) Asolution of 172.2 g. of hydroxynaphthoquinonyldecanoic acid in 1250 cc.of purified dioxane mixed with 60 g. of sodium carbonate in 1250 cc. ofwater is swept with a stream of pure nitrogen, 100 cc. of superoxol isadded, and the red solution heated in a bath at 67-70 C. untildecolorized (usually one or two hours). After cooling, 100 cc. of 36%hydrochloric acid is added, sulfur dioxide is bubbled in until an excessis noted by odor (about one hour), the excess is removed with a streamof nitrogen (two hours), and 400 g. of sodium hydroxide is added as asolution, followed by copper sulfate solution (458 g. of crystalspartially dissolved in 1 l. of water). The mixture is heated on thesteam bath for one-half hour, let stand at 25 C. for one-half hour, andfiltered through Super-Gel.

(The treatment with cold sul- The deep red solution is then slowlystirred into,

500 cc.'of 36% hydrochloric acid containing pieces of ice. The lightyellow precipitate melts at 116-118 C.; yield 120 g. (73%). Onecrystallization from acetic acid gave pure acid, M. P. 1245-1255 C. [seeFieser and Turner, J. Am. Chem. Soc., 69, 2338 (1947) Hydrolysis of thecorresponding ethyl ester in the oxidized form is not feasible becauseof sensitivity of the quinone ring to acids and bases.

The acid is obtained by reducing the ester in alcohol with aqueoushydrosulflte, extracting the hydroquinone from the ether with repeatedporyield 86% duction fluorescent. solution with silver oxide. Thequinone acid crystallizes from methanol Water .or dilute acetic acid inlight yellow needles, M. P. 109-110 C.

Hydrolysis is also accomplished by shaking a solution of 1 g. of esterin 10 cc. of acetic acid with 0.5 g. of zinc dust until the color islargely discharged, adding 3 cc. of water and 200. of 36% hydrochloricacid, heating for four hours on the steam bath, adding 0.5 g. of chromicanhydride, and diluting with water; M. P. 102- 103 (3., yield 0.90 g.

. The oxide, prepared as described in Example 3, separatesasmicrocrystals from either benzeneligroin or dilute methanol; M. P.99.5-100.5 C.

Sulfuric acid converts the oxide to the hydroxyquinone, M. P. 105,106 C.

EXAMPLE 7 Methyl w-(1,4 -naphthoquinonyZ-2) decanoate wl-h ydroxy-2-naphthyl) -decanoic acid is prepared from 2-sebacoyl-l-naphthol byhydrogenation over copper chromite at 100 C. and 3000 lbs.' and also byClemmensen-Martin re- (acetic acid-water-hydrochloric acidtoluene; yield72.3%). The acid is very soluble in acetone, benzene, or alcohol andslightly soluble in ligroin. Crystallization from benzeneligroin raisesthe M. P. to 96-97.5 C.

The methyl ester, prepared from 10 g. of acid,

cc. of methanol, and 1 cc. of boron fluoride etherate (refluxed onehour) and crystallized from ligroin, melts at -62 C.

y The -ethel ester prepared similarly, melts at Methyl w-(1,4-naphthoquinonyl-2) -decanoate,

prepared by oxidation of the naphthol ester, melts at 63-64 C.

EXAMPLE 8 Ethyl w (3-bromo-1,4-naphthaquinom1l-2 decanoate A mixture of35.6 g. of the quinone ester, 200.

cc. of acetic acid, 24 g. of anhydrous sodium acetate, and 6 cc. ofbromine is shaken in a glassstoppered flask for about six hours, oruntil all the sodium acetate has dissolved, and let stand in the darkfor eight days. The bromo ester that separates is collected (filtratesaved) Washed with 50% methanol, and crystallized from alcohol to give30.5 g. of material, M. P. 8788 C. The acetic acid mother liquor whendiluted with one volume of Water and let stand affords a precipitatethat is crystallized from the alcoholic mother liquor of the first cropto give 7 g. of serviceable product, M. P. 8587 C.; total The analyticalsample melts at 87.5-89 C.; the substance is light sensitive.

The following examples illustrate the production of various2-acylated-l-naphthols which may be converted to the correspondingsubstituted 1,4-naphthoquinones by successive reductionsj of :alkalinehydrosulflte (kryptophenol), ".{lhe complex is decomposed by boiling itwith extracting with ether, and shaking the blue tion of the keto groupand oxidation as described in Examples 2 and 3.

EXAMPLE 9 2- (4'-cyclohexylbutyryl) -l-napththol A mixture of 123 g. ofcyclohexylbutyric acid, 101 g. of a-naphthol, and 600 cc. of boronfluoride etherate is heated on the steam bath for five hours; water isadded and the mixture heated on the steam bath to remove ether andcooled.

alcohol and the product is crystallized from alco- 7 hoi to give 170 g.(80%) ofv the acylnaphthol, M'. P. 103-104" C.

EXAMPLE 1O 2- -p-phenoa:yphenylbutyi yl) -1-napththolv The procedure isthe same as in Example 9, using -p-phenoxyphenylbutyric acid the yieldof product, M. P. 121-123 C. from alcohol, is 90%.

EXAMPLE l1 Z-ZauroyZ-l-nqphthol This ketone is obtained in 82% yield bythe procedure of Example 9 usingzlauric acid; M P. 75-77 C. fromalcohol.

EXAMPLE l2 2-myristcyZ-1-naphthol The yield of ketone (M. P. 80-82 C.from. alcohol) by the procedure of Example 9 using myristic' acid is 83EXAMPLE 13. 2-w-bromoundecoyl-l-naphthol The procedure of Example 9using, w-bromoundecoic acid affords this ketone in 75% yield; M. P.104-105 C.

EXAMPLE l4 2-stearoyl-l-naphthol The same procedure (Exampe 9) usingstearic acid afiords this ketone in 72.6% yield. Crystallization fromdioxane-ethanol gives oblong plates, M. P. 87-88 C.

' EXAMPLE 15 2-octadecyZ-1-ndphthol Clemmensen reduction of the ketoneof Example 14 gives the crude alkylnaphthol (M. P. 64-67" C.) in 98%yield. On recrystallization from ethanol-water the substance formsyellowish plates, M. P. 6263.6 C.

8 I claim:

1. A method of making 1,4-naphthoquinonescontaining in the 2-position agroup selected from alkyland carboxyalkyl groups which comprisescondensing an acid of the group consisting of alkyl carboxylic acids,aralkyl carboxylic acids, and alkyl dicraboxylic acids with a-naphtholin thepresenceof a condensation catalyst, reducing the keto group of theketonaphthol thereby produced and oxidizing the resultant 2-substitutednaphthol to the corresponding lA-naphthoquinone with chromic acid.

2. A method of making w-(lA-naphthoquinonyl-Zl-decanoic acid whichcomprises condensing sebacic acid with A-naphthol in the presence of acondensation catalyst, reducing the keto group of the2-sebacoyl-l-naphthol thereby produced, and oxidizing the resultant2-carboxynonyl-l-naphthol to the corresponding 1,4- naphthoquinone withchromic acid.

3'. Inthe production of lA-napthoquinones containing an alkyl group inthe 2-position the step which comprises condensing an alkyl carboxylic'acid with w-naphthol in the-presence of boron fluoride to produce thecorresponding 2- acy1-1naphthol.

4. A method of producing 2-acyl-l-naphthols which comprises heating analkyl carboxylic acid with -naphthol in the presence of boron fluorideto produce the corresponding 2-acyl-naphthol.

GEORGE FAWAZ.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Name Date Fieser Apr. 16, 1946 OTHER REFERENCESNumber

1. A METHOD OF MAKING 1,4-NAPHTHOQUINONES CONTAINING IN THE 2-POSITION AGROUP SELECTED FROM ALKYL AND CARBOXYALKYL GROUPS WHICH COMPRISESCONDENSING AN ACID OF THE GROUP CONSISTING OF ALKYL CARBOXYLIC ACIDS,ARALKYL CARBOXYLIC ACIDS, AND ALKYL DICARBOXYLIC ACIDS WITH A-NAPHTHOLIN THE PRESENCE OF A CONDENSATION CATALYST, REDUCING THE KETO GROUP OFTHE KETONAPHTHOL THEREBY PRODUCED AND OXIDIZING THE RESULTANT2-SUBSTITUTED NAPTHOL TO THE CORRESPONDING 1,4-NAPHTHOQUINONE WITHCHROMIC ACID.